Alpha-cyano, alpha-alkyl glutaraldehydic acids



Patented Nov. 28, 1950 ALPHA-CYANO, ALPHA-ALKYL .GLUTARJAL DEHYDIC ACIDS...

Donald T. Warner and Owen A. Moe, Minneapolis,

Minn., assignors to General zlMi llsplnc', a.-cor'.-

poration of Delaware No Drawing. Application N ovemberfi; 1948,-

Serial No. 58318" 8 Claims.

The'-'present invention relates to variousiI'1ter-- mediate aldehyde compounds which are particu larly= useful'in' various organic-syntheses: The" aldehydes contemplated by the present invention may be represented by the following structural formulainto thereaction.-

2, it is preferred to operate at temperatures within the range of 30-50 C.

The reactionis carried out'in the presence of a-suitable-solvent diluent which does not enter W-hi'chmeetsthistest can be employed. Suitable solvents include alcohols-such as ethanol, ether-s ON suchas'diethyl'ether; and hydrocarbon solvents RL such asbenze'ne. The'amountofzsolventrems HR3 ployedmay be varied considerably. Usually it is desired to employer quantityfofi solvent at least (IJHO equals irrvolume to" the cyanoacetic ester emin which" Rl is the low alkyl group containing ployed. More ioften? thev amount of. solvent is several times the amount of the cyanoaceticester:

from one to four carbon atoms R2 is an In carrying outtthe reaction, it is preferred to aliphatic; hydrocarbon group containing from i 1 t cyanoacetlc estelilm one to twenty or more carbon atoms, and R and thglsolvent and to a t catalyst to the t R4 may be hydrogen or methyl The-resultant solut10n 1s-then. cooled to a suitable The aldehyde compounds of the present invenempemture dependmg upon the temperature tion are useful in numerous ways Inwiew of at whicniitiis:desired::to carry out the reaction. the high functionality of the molecule it islposgiffi i gt p i hl 1s ge q f q sible for them to enter into many typical organic i f Fgff"? :ififi $5 1 t 0 reactions and thus serve as useful intermediates t K s e m in further Organic Syntheses ure. 0 e reac 1011 Inn; ure very readily to I therefore n (Meet 5 t i Wm somewhere w1th1n uthetdesired'range and thus to tion r g e1 e'presen control the reaction .in the desired direction. in hpagove f y compoun After the reaction has been completed, the cata- It is a further object of the present invention :5? giggggj ff p oduct worked to novel process of producmg such 3 Ther'eactionis applicable to such alpha,beta- $gs1 aidehydes way be prepared by t e 1 4 unsaturated aldehydes as acrolein, methacrolein,

H 1 a l and crotonaldehyde. The alcoholic group of i fi g of 2 g g g esters to the'cyanoaceticester may be either methyL'ethyl, i 51- l 8 d ty id g a fl g t; proptyL. or 'butyl; However, inasmuch as cyanosar: .22 dressers a r rr m desired aldehyde. These reactions are carried ggl fi g r y ii g g z gg g gg sgfi i out.i1I1Et1l' 1e..prs1enc111{ of 'm alfiaifine cattalyst s11?! stituenton thecyanoacetic ester methylene group as a a 1 me a 2; 0X1 e.v e reac 1011 con 1- may be varied from one to twenty or more cartions aresublect to considerable variation de- 40 bun-1 atoms. L Iany of these cyanoacetic ester pending upon the reactants and the amount and compounds having aliphatic hydrocarbon subtype of catalyst employed. In general, best yields stituents on the methylene carbon are known thgaldeglylgej obtiginedgwhen gndreporteld'gnftjllile literature. Any of them can e amoun 0 0a ays- 1s ewi t e apeprepare y econ ensation-reduction reproximate rangezofiiOfiOlto 0.10 mole=per mole of actioniofthe'aliphatic aldehyd'etwith cyanoacetic reagent used: ester under knownl conditions.

Thetemperatureaemployediduring the a'ddition Thefollowing'examples will serve to illustrate reaction is subject to change depending upon the invention other. conditions; Under some-circumstances =a temperature'of 04090;may bedesirable; Under Example 1 h r cir c he re c ion proceedsf very A solution-of sodium etho-Xide was prepared scmooghly' azlild'rapidly gat.ten peratures un t0 from 50 m1. absolute ethanol and'fiofi g.- ofson ay iolwieesrgfei rggzggrgesfiagotgeio (ii ;lo--tl11s 53113301151 ig lhyl-butylcyancacetate 1 a er --g-; was a e an 9 mixture was cooled not to exceed this temperature, andimgeneral, as to +'8'- C? The cooled reaction medium was then Almost any solvent diluent treated with crotonaldehyde (7.05 g.) added dropwise. After a reaction time of one hour, the catalyst was neutralized with 0.5 ml. of glacial acetic acid, and the excess of solvent was removed in vacuo, leaving gamma-butyl-gamma-cyanogamma-carbethoxy beta methyl butyraldehyde as an oil.

The crude oil was dissolved in benzene, and the benzene solution was washed with water. The benzene was then removed in vacuo and gamma butyl gamma cyano gamma carbethoXy-beta-methyl-butyraldehyde was distilled at 98-109 C./0.2 mm.

Calcd. for C13H2103NI N, 5.85. Found: N, 6.09.

The gamma butyl gamma cyano gammacarbethoxy-beta-methyl-butyraldehyde was further characterized as the 2,4-dinitrophenylhydrazone melting at 1738-1745 C.

Calcdfor C19H25O6N'52 C, 54.41; H, 6.01; N, 16.70. Found: C, 54.33; H, 6.10; N, 16.91.

Example 2 A solution of sodium ethoxide was prepared from 40 ml. of ethanol and 0.04 g. of sodium. This solution was mixed with ethyl butylcyanoacetate (16.9 g.) and cooled to +4 C. Acrolein (5.89 g.) was added dropwise, and the reaction was allowed to continue for an addi tional 35 minutes at +5 C. The catalyst was then neutralized with 0.6 g. of glacial acetic acid, and the reaction mixture was concentrated in vacuo to obtain gamma-butyl-gamma-cyanogamma-carbethoxy-butyraldehyde as a thin syrup.

The crude aldehydo compound was dissolved in benzene and washed with water. The benzene layer was then concentrated in vacuo to remove benzene, and gamma-butyl -gamma-cyanogamma-carbethoxybutyraldehyde was collected at 100-115 C./0.26-0.56 mm. This compound was further characterized as the 2,4-dinitrophenylhydrazone melting at Ell-92 C. after crystallization from ethyl acetate and alcohol.

Calcd. for C'mHzsOeNe: C, 53.34; H, 5.72; N, 17.28. Found: C, 53.19; H, 5.71; N, 17.71.

Example 3 A solution of sodium ethoxide (from 50 ml. abs. EtOH and 0.05 g. of sodium) was mixed with ethyl butylcyanoacetate (16.9 g.) and the mixture was cooled to 1 C. Then alphamethylacrolein (7.0 g.) was added dropwise over a -minute period. The reaction mixture was cooled for an additional period of approximately 16 hours. The catalyst was neutralized with glacial acetic acid (0.5 g.) and the excess ethanol was removed by distillation in vacuo. The residual viscous oil was dissolved in benzene (100 ml.) and the benzene solution was washed with four 50 ml. portions of water. The benzene solution was then dried over 20 g. of anhydrous NaaSO4, and the benzene was removed by distillation. The residual oil was distilled, and the aldehydo compound, gamma butyl gamma cyano-gammacarbethoxy alpha methyl butyraldehyde, was collected at 90-100 C. (0.12-0.15 mm.) 11 1.4442. The gamma butyl gamma cyanogamma carbethoxy alpha methylbutyraldehyde was further characterized as its 2,4- dinitrophenylhydrazone which melted at 141.5- 142.5 C. after crystallization from an ethanolethylacetate solvent mixture.

As has been indicated previously, the various aldehyde compounds of the present invention are useful in further syntheses in view of the high functionality of the molecule. For example, they are useful in the synthesis of substituted biotins in accordance with the following generally indicated synthesis. The product of this reaction may be converted to substituted biotins in accordance with known reactions.

Aldehyde compounds of the present invention are also useful in the synthesis of substituted pimelic acids and also in the synthesis of hydantoins in accordance with the following series of reactions:

These compounds are also useful in the synthesis of beta-(3-indole)-propionic acids in accordance with the following reaction:

These aldehydes may also be used for the synthesis of amino acids by reacting them with HCN which reacts with the aldehyde group to form the cyanhydrin. This compound then may be reacted with ammonia to convert the hydroxyl group to an amino group, after which the resultant compound may be subjected to hydrolysis and decarboxylation to produce various amino acids.

The present invention is a continuation-in-part of our copending application, Serial No. 714,645, filed December 6, 1946, entitled Aldehydes, now abandoned.

While various modifications of the invention have been described, it is to be understood that other variations are possible without departing from the spirit thereof.

We claim as our invention:

1. Aldehyde compounds having the following formula in which R is an alkyl group containing from one to four carbon atoms, R is an aliphatic hydrocarbon group, and R and R are selected from the group consisting of hydrogen and methyl.

2. Aldehyde compounds having the following formula in which R is an alkyl group containing from one to four carbon atoms, and R is an aliphatic hydrocarbon group.

3. Aldehyde compounds having the following formula in which R is an alkyl group containing from one to four carbon atoms, R is an aliphatic hydrocarbon group, and R. is selected from the group consisting of hydrogen and methyl.

4. Aldehyde compounds having the following formula 5. Aldehyde compounds having the following formula JHE in which R is an alkyl group containing from one to four carbon atoms, R is a lower aliphatic hydrocarbon group, and R and R are selected from the group consisting of hydrogen and methyl.

6. Process of preparing aldehyde compounds having the following formula (:JHR CHIN CEO in which R is an alkyl group containing from one to four carbon atoms, R. is an aliphatic hydrocarbon group, and R and R are selected from the group consisting of hydrogen and methyl, which comprises adding a cyanoacetic ester having an aliphatic hydrocarbon substituent to an alpha,beta-unsaturated aldehyde selected from the group consisting of acrolein, methacrolein, and crotonaldehyde, in the presence of an organic solvent diluent and in the presence of an alkaline condensation catalyst.

7. Process of preparing aldehyde compounds having the following formula ON RLCCOOR1 oHR +11 CHO in which R is an alkyl group containing from one to four carbon atoms, R is an aliphatic hydrocarbon group, and R and R are selected from the group consisting of hydrogen and methyl, which comprises preparing a solution of a cyanoacetic ester having an aliphatic hydrocarbon substituent, in an organic solvent diluent containing an alkaline condensation catalyst, gradually adding thereto an alpha,beta-unsaturated aldehyde selected from the group consisting of acrolein, methacrolein, and crotonaldehyde, and maintaining the temperature of the reaction mixture not substantially in excess of 50 C.

8. Process of preparing aldehyde compounds having the following formula -GOOR1 OHR3 (BER

l CHO in which R is an alkyl group containing from one to four carbon atoms, R is an aliphatic hydrocarbon group, and R and R are selected from the group consisting of hydrogen and methyl, which comprises forming a solution of a cyanoacetic ester having an aliphatic hydrocarbon substituent, in an organic solvent diluent containing an alkali metal alkoxide in a molar ratio within the approximate range of 0.001 to 0.1 based on the cyanoacetic ester, gradually adding thereto an alpha,beta-unsaturated aldehyde selected from the group consisting of acrolein, methacrolein, and crotonaldehyde, and maintaining the temperature of the reaction mixture at not in excess of 50 C.

The following references are of record in the file of this patent:

UNITED STATES PATENTS Name Date Hamann Sept. 21, 1937 Numb er 

1. ALDEHYDE COMPOUNDS HAVING THE FOLLOWING FORMULA 